Project Summary/Abstract Alzheimer`s Disease (AD), is a severe neurodegenerative disorder characterized by progressive memory loss, language deficits, personality changes, and dementia, most prevalent in patents over 65. Current treatments only have modest and temporary effects on cognitive decline, highlighting the need for novel treatments which can halt the progression of AD. While familiar AD is caused by autosomal dominant mutations in amyloid precursor protein and presenilin, the majority of AD cases are considered sporadic with a combination of both genetic and environmental risk factors. However, amyloid-beta (A?) plaques, hyper-phosphorylated tau neurofibrillary tangles (NTs), and severe gliosis are all neurodegenerative hallmarks common to all forms of AD. The receptor for advanced glycation end-products (RAGE) is upregulated in the brains of AD patients and interacts directly with A? in neuronal, immune and vascular cells. RAGE signaling can also induce hyper-phosphorylation of tau and is implicated in the pathogenesis of co-morbid risk factors for sporadic AD (e.g. cardiovascular disease and diabetes). Thus, RAGE is a prime target for therapeutic development in both familial and sporadic AD. The RAGE pre-mRNA yields mutually exclusive alternative splice variants that are either, membrane- bound and capable of signaling (mbRAGE), or truncated and endogenously secreted to clear RAGE ligands without signaling (esRAGE). In AD mice, overexpression of mbRAGE accelerated the pathologic, cognitive, and behavioral hallmarks of AD, and infusion of synthetic esRAGE decreased A? and NT pathology as well as improved learning/memory and synaptic function. Thus, a novel strategy to reduce RAGE signaling is develop compounds called splice modulating oligonucleotides (SMOs) capable of controlling pre-mRNA alternative splicing to decrease expression of mbRAGE and simultaneously increase expression of esRAGE. SMOs are a class of synthetic RNA based compounds that sterically block or weaken interactions between elements of the splicing machinery and the pre-mRNA. SMOs bind to their targets with exceptional potency, specificity, long duration of action and negligible off-target effects. Previous pharmacological approaches to target ligand- RAGE interactions have been hampered by off-target effects or a short half-life, and none have the dual mechanism of both increasing natural esRAGE and decreasing mbRAGE isoform expression proposed here. SMOs targeting RAGE will be designed in silico and refined for potency and specificity, first in vitro cell culture (Aim 1) to select lead SMO drug candidates. Each SMO candidate will then be characterized and further optimized for safety and potency in vivo in RAGE transgenic mice (Aim 2). Finally, SMOs will be evaluated as therapeutics in an acute streptozotocin (STZ) induced model of AD for prevention/reversal of cognitive deficits and tau hyper-phosphorylation (Aim 3). The ultimate goal is to develop a lead RAGE SMO as potential therapeutic for the treatment of AD.